Enterococcal infective endocarditis (IE), of which 90% are due to E. faecalis, is the third most common cause of IE. This infection predominantly affects elderly patients and particularly in the U.S., has become a disease associated with healthcare contact. Despite its high profile as a cause of IE, antibiotic treatment regimens for enterococcal IE are suboptimal. Enterococci are relatively resistant to cell wall active agents such as penicillin, ampicillin, and vancomycin and are also relatively impermeable to aminoglycosides. Thus the killing of susceptible strains usually requires the synergistic action of a combination of a cell wall active agent (e.g., ampicillin) and an aminoglycoside (e.g. gentamicin). The American Heart Association and international guidelines recommend 4-6 weeks of penicillin or ampicillin plus an aminoglycoside for treatment of endocarditis caused by ampicillin and gentamicin susceptible Enterococci. This regimen is problematic because it comes with significant risk of nephrotoxicity (renal failure as high as 44% in the elderly) and because the prevalence of high level of resistance to aminoglycosides (HLAR) is increasing. There are compelling in vitro and in vivo experiments as well as two recently published observational clinical studies that suggest that the combination of ampicillin plus ceftriaxone (AC) is an alternative treatment regimen that has similar efficacy to the standard regimen of ampicillin plus gentamicin (AG) and has the benefit of avoiding significant nephrotoxicity. We propose a planning grant to perform a randomized clinical trial to test the hypothesis that the cure rate of patients treated with AC is non-inferior to the cure rate of patients treated with AG for E. faecalis IE. Secondary outcomes will be incidence of nephrotoxicity and cost. We will leverage the International Collaboration on Endocarditis (ICE), the single, largest multi-national consortium of IE investigators, and the Duke Clinical Research Institute (DCRI), the largest academic research institute in the world to execute the planning and subsequently, implementation, of this trial.